Suprastapled Peptides: Hybridization-Enhanced Peptide Ligation and Enforced α-Helical Conformation for Affinity Selection of Combinatorial Libraries,Journal of the American Chemical Society

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Suprastapled Peptides: Hybridization-Enhanced Peptide Ligation and Enforced α-Helical Conformation for Affinity Selection of Combinatorial Libraries
Journal of the American Chemical Society ( IF 14.4 ) Pub Date : 2021-11-05 , DOI: 10.1021/jacs.1c07013
Pramod M Sabale ₁ , Mateusz Imiołek ₁ , Pierre Raia ₁ , Sofia Barluenga ₁ , Nicolas Winssinger ₁

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Stapled peptides with an enforced α-helical conformation have been shown to overcome major limitations in the development of short peptides targeting protein–protein interactions (PPIs). While the growing arsenal of methodologies to staple peptides facilitates their preparation, stapling methodologies are not broadly embraced in synthetic library screening. Herein, we report a strategy leveraged on hybridization of short PNA–peptide conjugates wherein nucleobase driven assembly facilitates ligation of peptide fragments and constrains the peptide’s conformation into an α-helix. Using native chemical ligation, we show that a mixture of peptide fragments can be combinatorially ligated and used directly in affinity selection against a target of interest. This approach was exemplified with a focused library targeting the p-53/MDM2 interaction. One hundred peptides were obtained in a one-pot ligation reaction, selected by affinity against MDM2 immobilized on beads, and the best binders were identified by mass spectrometry.

中文翻译：

Suprastapled Peptides：杂交增强肽连接和强制α-螺旋构象用于组合文库的亲和力选择

具有强制α-螺旋构象的钉合肽已被证明可以克服针对蛋白质-蛋白质相互作用 (PPI) 的短肽开发中的主要限制。虽然越来越多的主肽方法有助于它们的制备，但合成文库筛选并未广泛采用装订方法。在这里，我们报告了一种利用短 PNA-肽缀合物杂交的策略，其中核碱基驱动的组装促进肽片段的连接并将肽的构象限制为 α-螺旋。使用天然化学连接，我们表明肽片段的混合物可以组合连接并直接用于针对感兴趣目标的亲和力选择。这种方法以针对 p-53/MDM2 相互作用的集中库为例。

更新日期：2021-11-17

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